Hexahydrodibenzofuran carboxylic acid derivatives

ABSTRACT

This invention is directed to certain dibenzofurancarboxamides and their use as 5HT 3  antagonists having unique CNS, anti-emetic and gastric prokinetic activity void of any significant D 2  receptor binding properties. This invention also describes novel processes necessary for their preparation.

This application is a divisional of Ser. No. 186,824 filed Apr. 27,1988, now U.S. Pat. No. 4,863,921.

FIELD OF THE INVENTION

This invention is directed to certain specific novel chemical compoundsand their valuable use as pharmaceutical agents as 5HT₃ antagonistshaving unique CNS, anti-emetic and gastric prokinetic activity void ofany significant D₂ receptor binding properties. This invention alsodescribes novel processes necessary for their preparation.

SUMMARY OF THE INVENTION

This invention relates to the compounds described by general Formula Iand to therapeutic compositions comprising as active ingredient acompound of Formula I: ##STR1## where R₁ is hydrogen, amino oralkylamino, halo;

R₂ is hydrogen, halo, sulfamyl, alkylsulfamyl or alkylsulfonyl;

R' is hydrogen or alkyl or together with a vicinal R' group may form adouble bond; and

R is ##STR2## and pharmaceutically acceptable salts thereof.

The following nomenclature is used in the description of this invention.##STR3## which refers to saturated, partially saturated and unsaturatedcompounds described herein. Preferred compounds of this inventioninclude those compounds of Formulae II, III and IV. ##STR4## where R₁and R₂ are as described above and R is ##STR5##

More preferred compounds include those of Formulae II, III and IV where

R₁ is amino, loweralkylamino or halo and R₂ is hydrogen;

R₁ is hydrogen and R₂ is halo, or

R₁ is amino and R₂ is halo.

The most preferred compounds include those of Formula II and especiallywhere halo is chloro or bromo and loweralkyl is methyl.

The present compounds may be prepared by the following generalprocedure. ##STR6##

Condensation of a substituted dibenzofuran-4-carboxylic acid or a6,7,8,9-tetrahydrodibenzofuran-4-carboxylic acid or a5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid or their acidhalides or esters with an amine of the formula H₂ N-R results in thecorresponding carboxamide.

In general this reaction may be carried out at decreased temperatures,such as 0° C. by adding ethyl chloroformate to a reaction mixture of theacid in chloroform in the presence of triethylamine. This is thenreacted with the amine of the formula H₂ N-R to obtain the desiredproduct. Condensation may also be carried out in the presence of adehydrating catalyst such as a carbodiimide in a solvent at normaltemperatures.

The starting materials, that is the substituteddibenzofuran-4-carboxylic acids,6,7,8,9-tetrahydrobenzofuran-4-carboxylic acids and the5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acids are also novel.They may be prepared by the following reaction schemes. ##STR7##

Salicylic acid is first esterified and then the phenol(2) is treatedwith 3-bromocyclohexene under basic conditions in a polar medium toobtain the phenyl cyclohexenyl ether(3), Claisen rearrangement at hightemperature results in the methyl 3-(3'-cyclohexene)salicylate(4). Ringclosure using trifluoroacetic acid results in the formation of the5a,6,7,8,9,9a-hexahydrodibenzofuran ring(5). This may then be hydrolyzedto the acid (6) with aqueous base.

When the 5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylate(5) isoxidized with DDQ, dichlorodicyanoquinone, the resultant double bond ofthe furan ring is formed to obtain6,7,8,9-tetrahydrodibenzofuran-4-carboxylate(7). Excess DDQ can resultin the unsaturated dibenzofuran-4-carboxylate product(8). ##STR8##

Dehydrogeneration of 6,7,8,9-tetrahydrodibenzofuran-4-carboxylate(7)with palladium on carbon catalyst at raised temperatures (230°-240° C.)results in the dibenzofuran-4-carboxylate(8). ##STR9##

Deesterification of the esters 7 and 8 may be carried out with aqueousbase, as above. ##STR10##

When R₂ substituted is desired the above reactions may be carried outstarting with the proper 5-substituted salicyclic acid. Thus thefollowing reaction sequences may take place as above. ##STR11##

When R₁ substitution is halo the above reaction sequence may be carriedout starting with 4-halo salicyclic acid.

In the case where R₂ is sulfamyl it is best that this group be protectedinitially with an acetyl group or the like and then deacetylated.

When R₁ is an amine function this also should be protected with anacetyl group or the like and then deacetylated after the dibenzofuranring system has been formed.

Treatment of a 4-amino or 4-alkylamino salicylic acid with MeOH/HClfollowed by acetylation with acetyl chloride in pyridine in the usualmanner results in the 4-acetylamino or4-acetylalkylaminosalicylates(14). Demethylation of the alcohol andester is then carried out using boron tribromide in a non polar solventto obtain the 4-acetylamino or 4-acetylalkylaminosalicylic acids(15).Esterification is accomplished with diazomethene as before and theresultant ester is used in a similar manner as above to obtain thedesired 1-amino or alkylamino dibenzofuran-4-carboxylic acidcompounds(18, 21, and 24). ##STR12## where R is H or alkyl.

In a similar manner, when R₁ and R₂ are both substituted with groupsother than hydrogen the following reaction sequences are possible toobtain compounds 27, 30 and 33. ##STR13##

When it is desired to have R' substitution of lower alkyl then asuitable starting material should be used. Thus for example if the finalproduct desired is1-amino-2-chloro-8-methyl-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylicacid(34) then 3-bromo-5-methylcyclohexene should be used as reagent inplace of 3-bromocyclohexene. ##STR14##

Following the above sequence of steps of the final product would be##STR15##

In a similar manner other compounds having R' substitution may beprepared.

When the 4-carboxylic acids 6, 9 and 10 are treated withN-chlorosuccinic or N-bromosuccinimide in a polar medium (DMF) at roomtemperature, the resulting halogenated products 11, 12 and 13 areformed. ##STR16## where X is cloro or bromo.

Halogenation may also be carried out on the 1-acetylamino compounds ofthe esters 16, 19 and 22. Halogenation occurs in the 2-position. Whenthese halogenated products are treated with base as above, hydrolysisgives the desired 1-amino-2-halo-4-carboxylic acids 27, 30 and 33 ofthis invention. ##STR17##

Certain compounds of this invention have at least one asymmetric carbonatom, such as the 5a,6,7,8,9,9a-hexahydrodibenzofuran compounds or thosecompounds wherein at least one R' is other than hydrogen or still thosecompounds were the R group contains an asymmetric carbon atom. As aresult, those compounds of Formula I may be obtained either as racemicmixtures or as individual enantiomers. When two asymmetric centers arepresent the product may exist as a mixture of two diasteromers. Theproduct may be synthesized as a mixture of the isomers and then thedesired isomer separated by conventional techniques such aschromatography or fractional crystallization from which eachdiasteriomer may be resolved. On the other hand, synthesis may becarried out by known sterospecific processes using the desired form ofthe intermediate which would result in obtaining the desiredspecificity.

In the case where R contains an asymmetric carbon atom it is convenientto carry out condensation of5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid with3-amino-1-azabicyclo-[2.2.2.]-octane or the like using the sterospecificmaterials. Thus, the hexahydrodibenzofuran-4-carboxylic acid is resolvedprior to condensation with resolved 3-aminoquinuclidine.

Further, certain compounds of this invention may exist in their cis ortrans configuration with respect to the furan ring.

The compounds of this invention may be readily converted to theirnon-toxic acid addition salts by customary methods in the art. Thenon-toxic salts of this invention are those salts the acid component ofwhich is pharmacologically acceptable in the intended dosages, includingthose prepared from inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, andfrom organic acids such as methane sulfonic acid, benzenesulfonic acid,acetic acid, propionic acid, maleic acid, oxalic acid, succinic acid,glycolic acid, lactic acid, salicylic acid, benzoic acid, nicotinicacid, phthalic acid, stearic acid, oleic acid, abietic acid, etc.

We have found that the compounds of this invention have gastricprokinetic and anti-emetic properties and lack D₂ -receptor bindingactivity. As such they possess therapeutic value in the treatment ofupper bowel motility and gastroesophageal reflux disorders. Further, thecompounds of this invention may be useful in the treatment of disordersrelated to impaired gastrointestinal motility such as retarted gastricemptying, dyspepsia, flatulence, esophageal reflux, peptic ulcer andemesis. The compounds of this invention exhibit 5-HT₃ antagonism and areconsidered to be useful in the treatment of psychotic disorders such asschizophrenia and anxiety and in the prophylaxis treatment of migraineand cluster headaches. We have further found that these compounds areselective in that they have little or no dopaminergic antagonistactivity.

Various tests in animals can be carried out to show the ability of thecompounds of this invention to exhibit pharmacological responses thatcan be correlated with activity in humans. These tests involve suchfactors as the effect of the compounds of Formula I on gastric motility,emesis, selective antagonism of 5-HT₃ receptors and their D₂ dopaminereceptor binding properties.

It has been found that the compounds of this invention when tested inthe above variety of situations show a marked activity.

One such test is the "Rat Gastric Emptying: Amberlite Bead Method". Thistest is carried out as follows:

The study is designed to assess the effects of a test agent on gastricemptying of a solid meal in the rat. The procedure is a modification ofthose used in L. E. Borella and W. Lippmann (1980) Digestion 20: 26-49.

Procedure

Amberlite® beads are placed in a phenol red solution and allowed to soakfor several hours. Phenol red serves as an indicator, changing the beadsfrom yellow to purple as their environment becomes more basic. Aftersoaking, the beads are rinsed with 0.1 NaOH to make them purple and thenwashed with deionized water to wash away the NaOH.

The beads are filtered several times through 1.18 and 1.4 mm sieves toobtain beads with diameters in between these sizes. This is done usinglarge quantities of deionized water. The beads are stored in salineuntil ready to use.

Male Sprague-Dawley rats are fasted 24 hours prior to the study withwater ad libitum. Rats are randomly divided in treatment groups with anN of 6 or 7.

Test agents are prepared in 0.5% methylcellulose and administered to therats orally in a 10 ml/kg dose volume. Control rats receive 0.5%methylcellulose, 10 ml/kg p.o. One hour after dosing, rats are given 60Amberlite® beads intragastrically. The beads are delivered via a 3 inchpiece of PE 205 tubing attached to a 16 gauge tubing adapter andsyringe. A small piece of PE 50 tubing is placed inside the tubingadapter to prevent the beads from being pulled back into the syringe.The beads are flushed into each rat's stomach with 1 ml saline.

Rats are sacrificed 30 minutes after receiving the beads and theirstomachs are removed. The number of beads remaining in each stomach iscounted after rinsing the beads with NaOH.

The number of beads remaining in each stomach is subtracted from 60 toobtain the number of beads emptied. The mean number of beads ±S.E.M. isdetermined for each treatment group. The percent change from control iscalculated as follows: ##EQU1##

Statistical significance may be determined using a t-test forindependent samples with a probability of 0.05 or less considered to besignificant.

In order to demonstrate the ability of the compounds of this inventionas anti-emetic agents the following test for "Cisplatin-Induced Emesisin the Ferret" may be used. This test is a modified version of a paperreported by A. P. Florezyk, J. E. Schurig and W. T. Brodner in CancerTreatment Reports: Vol. 66, No. 1. January 1982.

Cisplatin had been shown to cause emesis in the dog and cat. Florczyk,et al. have used the ferret to demonstrate the same effects.

Procedure

Male castrated, Fitch ferrets, weighing between 1.0 and 1.5 kg have anin Indwelling catheter placed in the jagular vein. After a 2-3 dayrecovery period, the experimental procedure is begun.

30 minutes prior to administration of cisplatin, ferrets are dosed withthe compound in 0.9% saline (i.v.) at a dose volume of 2.0 ml/kg.

45 minutes after administration of cisplatin, ferrets are again dosedwith the 0.9% saline (i.v.) mixture at a dose volume of 2.0 ml/kg.

Cisplatin is administered (i.v.) 30 minutes after the first dosing withthe 0.9% saline. Cisplatin, 10 mg/kg is administered in a dose volume of2.0 ml/kg.

The time of cisplatin administration is taken as time zero. Ferrets areobserved for the duration of the experiment (4 hours). The elapsed timeto the first emetic episode is noted and recorded, as are the totalnumber of periods of emesis.

An emetic (vomiting) episode is characterized by agitated behavior, suchas pacing around the cage and rapid to and fro movements. Concurrentwith this behavior are several retching movements in a row, followed bya single, large, retch which may or may not expulse gastric contents.Immediately following the single large retch, the ferret relaxes. Singlecoughs or retches are not counted as vomiting episodes.

D-2 Dopamine Receptor Binding Assay

The D-2 dopamine receptor binding assay has been developed with slightmodifications using the method of Ian Cresse, Robert Schneider andSolomon H. Snyder, Europ. J. Pharmacol. 46: 377-381(1977). Spiroperidolis a butyrophenone neuroleptic whose affinity for dopamine receptors inbrain tissue is greater than that of any other known drug. It is ahighly specific D-1 dopamine (non-cyclase linked) receptor agent with K₁values of 0.1-0.5 for D-2 inhibition and 300 nM for D-1 inhibition.

Sodium ions are important regulators of dopamine receptors. The affinityof the D-2 receptor is markedly enhanced by the presence of millimolarconcentrations of sodium chloride. The Kd in the absence and presence of120 mM sodium chloride is 1.2 and 0.086 nM respectively. Sodium chloride(120 mM) is included in all assays as a standard condition.

The caudate nucleus (corpus striatum) is used as the receptor sourcebecause it contains the highest density of dopamine receptors in thebrain and periphery.

Procedure

Male Charles-River rates weighing 250-300 g are decapitated and theirbrains removed, cooled on ice, and caudate dissected immediately andfrozen on dry ice. Tissue can be stored indefinitely at -70° C. Forassay caudate is homogenized in 30 ml of tris buffer (pH 7.7 at 25° C.)using the polytron homogenizer. The homogenate is centrifuged at 40,000g (18,000-19,000 RPM in SS-34 rotor) for 15 minutes. Pellet isresuspended in fresh buffer and centrifuged again. The final pellet isresuspended in 150 volumes of assay buffer.

Specific ³ H-spiroperidol binding is assayed in a total 2 ml reactionvolume consisting of 500 μl of caudate homogenate, 50 mM tris buffer (pH7.4 at 35° C.), 5 mM MgSO₄, 2 mM EDTA.2NA, 120 mM NaCl, 0.1% ascorbicacid, 0.4 nM ³ H-spiroperidol and test compound or assay buffer. Whencatecholamines are included in the assay, 10 μM pargyline should beincluded in the reaction mixture to inhibit monoamine oxidase. Samplesare incubated at 37° C. for 30 minutes followed by addition of 5 ml icecold 50 mM TRIS (pH 7.7 at 25° C.) and filtration through GF/B glassfiber filters on a Brandel Receptor Binding Filtration apparatus.Filters are washed twice with an additional 5 ml of tris buffer each.Assay groups are performed in triplicate and 1 μM d(+) butaclamol isused to determine nonspecific binding. Filters are placed in vialscontaining 10 ml of Ecoscint phosphor, shaken for 30 minutes and dpmdetermined by liquid scintillation spectrophotometry using a quenchcurve. Proteins are determined by the method of Bradford, M. Anal.Biochem 72, 248(1976) using Bio-Rad's coomassie blue G-250 dye reagent.Bovine gamma globulin supplied by BIO-RAD is used as the proteinstandard.

Bezold-Jarisch effect in anaesthetized rats

Male rats 260-290 g are anaesthetized with urethane 1.25 g/kg⁻¹ i.p.,and the trachea cannulated. The jugular vein is cannulated forintravenous (i.v.) injection of drugs. Blood pressure is recorded from acannula in the left carotid artery and connected to ahaparin/saline-filled pressure transducer. Continuous heart ratemeasurements are taken from the blood pressure recordings. TheBezold-Jarisch effect is evoked by rapid, bolus i.v. injections of 5-HTand measurements are made of the fall in heart rate. In each rate,consistent responses are first established with the minimum dose of 5-HTthat evokes a clear fall in heart rate. Injections of 5-HT are givenevery 12 minutes and a dose-response curve for the test compound isestablished by injecting increasing doses of compound 5 minutes beforeeach injection of 5-HT. The effect of the compound on the 5-HT-evokedbradycardia is calculated as a percent of the bradycardia evoked by 5-HTbefore injection of compound.

In separate experiments to measure the duration of 5-HT antagonismcaused by the compounds of this invention, a single dose of compound isinjected 5 minutes before 5-HT, and the effects of 7 repeated challengeswith 5-HT are then monitored. The effects of the compound on theefferent vagal limb of the Bezold-Jarisch reflex are checked byelectrically stimulating the peripheral end of a cut vagus nerve.Unipolar electrical stimulation is applied every 5 minutes via a pair ofsilver electrodes, using 1 ms rectangular pulses in 5 s trains with amaximally-effective voltage (20 V at 10 Hz). Pulse frequency may varyfrom 5-30 Hz and frequency-response curves are constructed before and 10minutes after i.v. injection of a single dose of compound.

The results of these above tests indicate that the compounds for thisinvention exhibit a valuable balance between the peripheral and centralaction of the nervous system and may be useful in the treatment ofdisorders related to impaired gastro-intestinal motility such as gastricemptying, dyspepsia, flatulence, esophogeal reflux and peptic ulcer andin the treatment of disorders of the central nervous system such aspsychosis.

The compounds of the present invention can be administered to amammalian host in a variety of forms adapted to the chosen route ofadministration, i.e., orally, or parenterally. Parenteral administrationin this respect includes administration by the following routes:intravenous, intramuscular, subcutaneous, intraocular, intrasynovial,transepthelially including transdermal, opthalmic, sublingual andbuccal; topically including opthalmic, dermal, ocular, rectal and nasalinhalation via insufflation and aerosol and rectal systemic.

The active compound may be orally administered, for example, with aninert diluent or with an assimilable edible carrier, or it may beenclosed in hard or soft shell gelatin capsules, or it may be compressedinto tablets, or it may be incorporated directly with the food of thediet. For oral therapeutic administration, the active compound may beincorporated with excipient and used in the form of ingestibe tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,and the like. Such compositions and preparations should contain at least0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be betweenabout 2 to about 6% of the weight of the unit. The amount of activecompound in such therapeutically useful compositions is such that asuitable dosage will be obtained. Preferred compositions or preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between about 50 and 300 mg of active compound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia, corn starch orgelating; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, patato starch, lginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills, or capsules may be coated with shellac,sugar or both. A syrup or elixir may contain the active compound,sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form should bepharmaceutically pure and substantially non-toxic in the amountsemployed. In addition, the active compound may be incorporated intosustained-release preparations and formulations.

The active compound may also be administered parenterally orintraperiotoneally. Solutions of the active compound as a free base orpharmacologically acceptable salt can be prepared in water suitablymixed with a surfactant such as hydroxypropylcellulose. Dispersion canalso be prepared in glycerol, liquid polyethylene glycols, and mixturesthereof and in oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that easy syringability exists. It may be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), suitable mixtures thereof,and vegetable oils. The proper fluidity can be maintained, for example,by the use of a coating such as lecithin, by the maintenance of therequired particle size in the case of dispersion and by the use ofsurfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimersal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions of agent delaying absorption, for example,aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredient into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vaccum drying and the freeze dryingtechnique which yield a powder of the active ingredient plus anyadditional desired ingredient from previously sterile-filtered solutionthereof.

The therapeutic compounds of this invention may be administered to amammal alone or in combination with pharmaceutically acceptablecarriers, as noted above, the proportion of which is determined by thesolubility and chemical nature of the compound, chosen route ofadministration and standard pharmaceutical practice.

The physician will determine the dosage of the present therapeuticagents which will be most suitable for prophylaxis or treatment and willvary with the form of administration and the particular compound chosen,and also, it will vary with the particular patient under treatment. Hewill generally wish to initiate treatment with small dosages by smallincrements until the optimum effect under the circumstances is reached.The therapeutic dosage will generally be from 0.1 to 20 mg or from about0.01 mg to about 50 mg/kg of body weight per day and higher although itmay be administered in several different dosage units from once toseveral times a day. Higher dosages are required for oraladministration.

The compounds of this invention may be prepared by the followingrepresentative examples.

The compounds of the present invention may be prepared by the followingrepresentative examples.

EXAMPLE 1 Methyl 5-chlorosalicylate

To a cold solution of 100 ml methanol is slowly added 100 ml thionylchloride followed by 30 g of 5-chlorosalicylic acid. This is thenrefluxed overnight, the solvent removed and the residue dissolved inether. The ether is washed with a sodium bicarbonate solution, water,dried over magnesium sulfate and evaporated to dryness to obtain methyl5-chlorosalicylate which is used directly in the next step.

EXAMPLE 2 Methyl 2-(cyclohexen-3-yloxy)-5-chlorobenzoate

A mixture of 18.6 g of methyl 5-chlorosalicylate, 28 g of K₂ CO₃ and 20g of 3-bromocyclohexene in 200 ml of DMF is stirred at 90° C. overnight.The mixture is then poured onto water, extracted with ethylacetate,washed with water, dried over magnesium sulfate and evaporated todryness to obtain crude product. This is purified by flashchromatography using hexane as the eluent to give pure methyl2-(cyclohexen-3-yloxy)-5-chlorobenzoate as the first fraction which isused directly in the next step.

EXAMPLE 3 Methyl 3-(3-hexenyl)-5-chlorosalicylate

Methyl 2-(cyclohexen-3-yloxy)-5-chlorobenzonate (4.5 g) is heated to210° C. for 3 hours. The residue is dissolved in hexane and purified byflash chromatography using first hexanes as eluent and then 5%ethylacetate/hexane to give pure methyl3-(3-hexenyl)-5-chlorosalicylate. This is used directly in the nextstep.

EXAMPLE 4 Methyl2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylate

A mixture of 2.2 g of methyl 3-(3-hexenyl)-5-chlorosalicylate and 5 mlof trifluoroacetic acid are stirred at room temperature overnight. Theacid is removed under vacuo and the residue diluted with ether, washedwith sodium bicarbonate solution, then water and dried over magnesiumsulfate and evaporated to dryness to give an oily product. Purificationby flash chromatography using hexane as eluent gives first unreactedstarting material and then methyl2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylate. This is useddirectly in the next step without further purification.

EXAMPLE 5 2-Chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid

A mixture of 1.6 g of methyl2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylate in 10 ml ofmethanol and 20 ml of 1N sodium hydroxide is stirred at 50° C. for 6hours. This is cooled, the methanol is removed under vacuo, diluted with30 ml water and filtered. The aqueous solution is acidified with aceticacid, extracted with ethyl acetate, washed with water, dried overmagnesium sulfate and evaporated to dryness to give crystalline productwhich is used directly in the next step.

EXAMPLE 62-Chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicyclo[2.2.2.]oct-3-yl)carboxamide

To a cold solution of 1.3 g of2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid in 40 mlof chloroform is added 0.8 g of triethylamine at room temperature. Tothis is added 0.7 g of ethylchloroformate in 10 ml of chloroform andstirring continued for 11/2 hours. This is added in one portion to amixture of 15 g K₂ CO₃ in 25 ml water containing 5 g of3-aminoquinuclidine dihydrochloride. Stirring is continued overnight.The reaction mixture is diluted with 100 ml chloroform and the organiclayer separated, washed twice with water, dried over magnesium sulfateand evaporated to dryness to give 1.2 g of oily product. The latter ispurified by flash chromatography using 10% methanol/chloroform whichresults in pure2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicylo-[2.2.2.]oct-3-yl)carboxylate.

Calculated: C 64.95; H 7.08; N 7.57; Found: C 64.24; H 6.72; N 7.02.

EXAMPLE 7

When 5-chlorosalicylic acid is replaced in Example 1 with salicylicacid, 5-bromosalicylic acid or 5-methylsulfonylsalicylic acid then theproducts prepared following the procedures of Examples 1-6 are5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicylo[2.2.2.]oct-3-yl)carboxamide;2-bromo-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicyclo[2.2.2.]oct-3-yl)carboxamide;and2-methylsulfonyl-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicyclo[2.2.2.]oct-3-yl)carboxamide.

EXAMPLE 8 Methyl 2-methoxy-4-amino-5-chlorobenzoate

To a solution of 50 g of 2-methoxy-4-amino-5-chlorobenzoic acid in 500ml of methanol is added HCl gas until all the material dissolves.Stirring is continued overnight, the solvent removed, ether added,filtered, dried over magnesium sulfate and evaporated to dryness toobtain methyl 2-methoxy-4-amino-5-chlorobenzoate which is used directlyin the next step.

EXAMPLE 9 Methyl 2-methoxy-4-acetylamino-5-chlorobenzoate

A mixture of 21 g of methyl 2-methoxy-4-amino-5-chlorobenzoate isstirred in 12 ml acetic anhydride and 100 ml acetic acid at 100° C. for24 hours. The reaction mixture is filtered, diluted with water, filteredand evaporated to dryness to obtain methyl2-methoxy-4-acetylamino-5-chlorobenzoate which is used directly in thenext step.

EXAMPLE 10 4-Acetylamino-5-chlorosalicylic acid

To a mixture of 16 g of methyl 2-methoxy-4-acetylamino-5-chlorobenzoatein 130 ml of methylene chloride is slowly added 100 ml of a methylenechloride solution of borontribromide (250 g BBr₃ per liter) and stirringcontinued for 24 hours. 1N sodium hydroxide solution is then added untilall material is dissolved. The two layers are separated and the aqueouslayer is acidified with 1N hydrochloric acid, filtered, washed withwater and evaporated to dryness to give 4-acetylamino-5-chlorosalicylicacid which is used directly in the next step.

EXAMPLE 11 Methyl 4-acetylamino-5-chlorosalicylate

To a mixture of 5 g of potassium hydroxide, 8 ml water and 25 ml ethanolat 0° C. (with no stirring) is slowly added a solution of 22 g Diazaldin 200 ml ether. The combination of diazomethane in ether which isdistilled over is cooled in an ice cold flask until the distillation iscomplete. To this solution is added 13 g of4-acetylamino-5-chlorosalicylic acid in 150 ml THF. After 1/2 hour theexcess diazomethane is decomposed by acetic acid and the mixturefiltered to obtain crude methyl 4-acetylamino-5-chlorosalicylate. Thefiltrate is concentrated to obtain further product which is combined andused directly in the next step.

EXAMPLE 12 Methyl 2-(cyclohexen-3-yloxy)-4-acetylamino-5-chlorobenzoate

A mixture of 2.5 g methyl 4-acetylamino-5-chlorosalicylate, 2 g of3-bromocyclohexene, 2 g K₂ CO₃ and 30 ml DMF are combined and heated at110° C. overnight. The reaction mixture is then poured into water,filtered, dried and then extracted into ether. The ether solution istreated with charcoal, filtered and evaporated to dryness to obtainmethyl 2-(cyclohexen-3-yloxy)-4-acetylamino-5-chlorobenzoate. This isthen purified by recrystallization from ether/hexane. (M.P. 100°-102°C.)

EXAMPLE 13 Methyl 3-(3-hexenyl)-4-acetylamino-5-chlorosalicylate

A mixture of 0.6 g of methyl2-(cyclohexen-3-yloxy)-4-acetylamino-5-chlorobenzoate and 0.5 mldiethylaniline is placed under house vaccum and heated to 220° C. for 2hours. This reaction mixture is then diluted with 40%ethylacetate/hexane and purified by dry column chromatography using thesame solvent system as eluent. Three fractions are separated: 1.diethylaniline; 2. starting benzoate compound and 3. methyl3-(3-hexenyl)-4-acetylamino-5-chlorosalicylate. The latter is useddirectly in the next step.

EXAMPLE 14 Methyl1-acetylamino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylate

A mixture of 1.2 g of methyl3-(3-hexenyl)-4-acetylamino-5-chlorosalicylate and 5 ml trifuloroaceticacid are stirred at room temperature overnight. The acid is removedunder vacuum and the residue diluted with ether, washed with sodiumbicarbonate, then water, dried and evaporated to dryness to give crudemethyl1-acetylamino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylate.This product is purified by flash chromatography using 10%ethylacetate/hexane to give pure product.

EXAMPLE 151-Amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid

To a solution of 0.3 g of sodium in 15 ml methanol is added 0.6 g ofmethyl1-acetylamino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylate.Stirring is continued at 60° C. for two days. This is then diluted with5 ml 1N sodium hydroxide and stirring continued at 60° C. overnight. Themethanol is removed in vacuum, diluted with water, filtered, acidifiedwith acetic acid, filtered, washed with water, dried over magnesiumsulfate and evaporated to dryness to obtain1-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid.This is purified by crystallization from ethyl acetate/ether.

EXAMPLE 161-Amino-2-chloro-5a,6,7,8,9,9a-hexahydroibenzofuran-4-(N-1-azabicylco[2.2.2.]oct-3-yl]carboxamide

To a cold solution of 0.3 g1-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acidin 40 ml chloroform is added 0.3 g of triethylamine and then 0.2 gethylchloroformate in 10 ml chloroform. Stirring is continued for 2hours. This is then added to a cold mixture of 3 g 3-aminoguinuclidinedihydrochloride in 20 ml water containing 7.5 g K₂ CO₃. Stirring iscontinued overnight. The reaction mxiture is then diluted withchloroform, the two layers separated and the chloroform layer washedtwice with water, dried over magnesium sulfate and evaporated to drynessto give1-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicylo[2.2.2.]oct-3-yl]carboxamideas an oily product.

Calculated: C 62.41; H 7.07; N 10.91; Found: C 62.84; H 7.00; N 10.63.

EXAMPLE 17

When 2-methoxy-4-amino-5-chlorobenzoic acid is replaced in Example 8with 2-methoxy-4-aminobenzoic acid;2-methoxy-4-methylamino-5-chlorobenzoic acid;2-methoxy-5-sulfamylbenzoic acid; or 2-methoxy-5-methylsulfamyl benzoicacid then the products prepared following the procedures of Examples8-16 are1-amino-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicylo[2.2.2.]oct-3-yl)carboxamide;1-methylamino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicyclo[2.2.2.]oct-3-yl)carboxamide;2-sulfamyl-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicyclo[2.2.2.]oct-3-yl)carboxamide;or2-methylsulfamyl-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicyclo[2.2.2.]oct-3-yl)carboxamide.

EXAMPLE 18

When 3-aminoquinuclidine dihydrochloride in Examples 6, 7, 16 and 17 isreplaced by the amines of Table I below, then the correspondingrepresentative carboxamides of Table II below are prepared.

                  TABLE I                                                         ______________________________________                                         3-aminoquinuclidine which is 3-amino-1-azabicyclo[2.2.2.]octane               ##STR18##                                                                    4-amino-1-azabicyclo[3.3.1.]nonane                                             ##STR19##                                                                    4-amino-1-azabicyclo[2.2.2.]octane                                             ##STR20##                                                                    3-amino-9-methyl-9-azabicylco[3.3.1.]nonane                                    ##STR21##                                                                    3-amino-7-oxo-9-methyl-9-azabicylo[3.3.1.]nonane                               ##STR22##                                                                    1-(p-fluorophenoxypropyl)-3-methoxy-4-aminopiperidine                          ##STR23##                                                                    ______________________________________                                    

TABLE II

2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(1-azabicyclo[3.3.1.]non-4-yl)carboxamide

2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(1-azabicyclo[2.2.2.]oct-4-yl)carboxamide

2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(9-methyl-9-azabicyclo[3.3.1.]non-3-yl)carboxamide

2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(7-oxo-9-methyl-9-azabicylo[3.3.1.]non-3-yl)carboxamide

2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(1-(p-fluorophenoxypropyl)-3-methoxypiperidin-4-yl)carboxamide

1-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(1-azabicyclo[3.3.1.]non-4-yl)carboxamide

1-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(1-azabicyclo[2.2.2.]oct-4-yl)carboxamide

1-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(9-methyl-9-azabicyclo[3.3.1.]non-3-yl)carboxamide

1-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(7-oxo-9-methyl-9-azabicylo[3.3.1.]non-3-yl)carboxamide

1-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(1-(p-fluorophenoxypropyl)-3-methoxypiperidin-4-yl)carboxamide

EXAMPLE 19

When 3-bromocyclohexene of Examples 2 and 12 is replaced by

3-bromo-4-methylcyclohexene

3-bromo-5-methylcyclohexene

3-bromo-6-methylcyclohexene

then the corresponding products are prepared following Examples 2-18.

EXAMPLE 20 Methyl1-acetylamino-2-chloro-6,7,8,9-tetrahydrodibenzofuran-4-carboxylate

A mixture of 1 g methyl1-acetylamino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylateand 1 g of dichlorodicyanoquinone in 15 ml of benzene is stirred andheated at 80° C. in a sealed tube for 8 hours. The coooled reactionmixture is then diluted with benzene, filtered and evaporated todryness. Purification by recrystallization from ethyl acetate/hexanegives pure methyl1-acetylamino-2-chloro-6,7,8,9-tetrahydrodibenzofuran-4-carboxylate.

EXAMPLE 21 Methyl 1-acetylamino-2-chlorodibenzofuran-4-carboxylate

A mixture of 1 g methyl1-acetylamino-2-chloro-6,7,8,9-tetrahydrodibenzofuran-4-carboxylate and0.5 g of 5% palladium-charcoal is heated under nitrogen at 230° C. for 5hours. The cooled residue is extracted with toluene and the solventevaporated to dryness. The residue is crystallized from ethylacetate/hexane to give methyl1-acetylamino-2-chlorodibenzofuran-4-carboxylate.

EXAMPLE 22 1-Amino-2-chloro-6,7,8,9-tetrahydrodibenzofuran-4-carboxylicacid 1-Amino-2-chlorodibenzofuran-4-carboxylic acid

When the procedure of Example 15 is followed however methyl1-acetylamino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylateis replaced by methyl1-acetylamino-2-chloro-6,7,8,9-tetrahydrodibenzofuran-4-carboxylate ormethyl 1-acetylamino-2-chlorodibenzofuran-4-carboxylate then thecaptioned products are prepared.

EXAMPLES 231-Amino-2-chloro-6,7,8,9-tetrahydrodibenzofuran-4-(N-1-azabicyclo[2.2.2.]oct-3-yl)carboxamide1-Amino-2-chlorodibenzofuran-4-(N-1-azabicyclo[2.2.2.]oct-3-yl)carboxamide

When the procedure of Example 16 is followed however,1-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acidis replaced by1-amino-2-chloro-6,7,8,9-tetrahydrodibenzofuran-4-carboxylic acid or1-amino-2-chlorodibenzofuran-4-carboxylic acid then the captionedproducts are prepared.

EXAMPLE 24 Methyl2-chloro-cis-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylate Methyl2-chloro-trans-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylate

A mixture of 9 g of methyl 3-(3-hexenyl)-5-chlorosalicylate and 20 mltrifluoroacetic acid is heated at 70° C. overnight. The cooled reactionmixture is diluted with hexanes, washed three times with water, driedand evaporated to dryness. The residue is purified with flashchromatography using 10% ethylacetate/hexane to give four fractions

first fraction 2.2 g of material (mixture of at least two materials)

second fraction 2.2 g cis isomer

third fraction 1.6 g mixture of cis and trans isomers

fourth fraction 1 g trans isomer

EXAMPLE 25 2-Chloro-cis-5a,6,7,8,9,9a-hexadrodibenzofuran-4-carboxylicAcid

A mixture of 2 g methyl2-chloro-cis-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylate in 30 ml1N sodium hydroxide and 5 ml dioxane is stirred at 60° C. for 5 hours.This is then diluted with water, filtered, acidified with acetic acid,extracted with ethyl acetate, dried over magnesium sulfate andevaporated to dryness to obtain an oily product which crystallizes onstanding. This is recrystallyzed to obtain2-chloro-cis-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid.(M.P. 132°-4° C.)

EXAMPLE 26

Following the procedure of Example 25 but using the trans isomer inplace of this cis, the corresponding2-chlor-trans-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid isprepared.

EXAMPLES 272-Chloro-cis-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicyclo[2.2.2.]oct-3-yl)carboxamide2-Chloro-trans-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicyclo[2.2.2.]oct-3-yl)carboxamide

Following the procedures of Examples 6 and 16 but substituting the cisand trans isomers of Examples 25 and 26, then the above captionedproducts are prepared.

EXAMPLE 281-Chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicyclo[2.2.2.]oct-3-yl)carboxamide

Following the procedures of Examples 1-6 but substituting4-chlorosalicylic acid in Example 1 for 5-chlorosalicylic acid, then theabove captioned carboxamide is prepared.

We claim:
 1. A compound of the formula ##STR24## where R₁ is hydrogen,amino, alkylamino or halo; R₂ is hydrogen, halo, sulfamyl; alkylsulfamylor alkylsulfonyl; R' is hydrogen or alkyl; and R₃ is hydroxy, halo,alkoxy or aralkoxy; provided that R', R₁ and R₂ are not all hydrogen atthe same time.
 2. A compound according to claim 1 which is: ##STR25## 3.A compound according to claim 2 where R₂ is halo.
 4. A compoundaccording to claim 2 where R₁ is amino.
 5. A compound according to claim2 where R₁ is amino and R₂ is halo.
 6. A compound according to claim 3where halo is chloro or bromo and R₃ is hydroxy.
 7. A compound accordingto claim 4 where R₃ is hydroxy.
 8. A compound according to claim 2 whereR₂ is chloro or bromo and R₃ is hydroxy.
 9. A compound according toclaim 1 which is in the 5a,9a cis configuration.
 10. A compoundaccording to claim 3 which is in the 5a,9a cis configuration.
 11. Acompound according to claim 10 which is2-chloro-cis-5a,6,7,8,9,9-hexahydrodibenzofuran-4-carboxylic acid.